Combination therapy comprising anti-diabetic and anticonvulsant agents

ABSTRACT

Combination therapy comprising anti-diabetic agents and anticonvulsant derivatives useful for the treatment of Type II diabetes mellitus and Syndrome X are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/244,225 filed Oct. 30, 2000, the contents ofwhich are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Type II (or Type 2) diabetes mellitus (non-insulin-dependentdiabetes mellitus or NIDDM) is a metabolic disorder involvingdysregulation of glucose metabolism and insulin resistance, andlong-term complications involving the eyes, kidneys, nerves, and bloodvessels. Type II diabetes mellitus usually develops in adulthood (middlelife or later), although it is increasingly reported in adolescents. Itis described as the body's inability to make either sufficient insulin(abnormal insulin secretion) or its inability to effectively use insulin(resistance to insulin action in target organs and tissues). Moreparticularly, patients suffering from Type II diabetes mellitus have arelative insulin deficiency. That is, in these patients, plasma insulinlevels are normal to high in absolute terms, although they are lowerthan predicted for the level of plasma glucose that is present.

[0003] Type II diabetes mellitus is characterized by the followingclinical signs or symptoms: persistently elevated plasma glucoseconcentration or hyperglycemia; polyuria; polydipsia and/or polyphagia;chronic microvascular complications such as retinopathy, nephropathy andneuropathy; and macrovascular complications such as hyperlipidemia andhypertension. These micro- and macro-vascular complications can lead toblindness, end-stage renal disease, limb amputation and myocardialinfarction.

[0004] Syndrome X, is also termed Insulin Resistance Syndrome (IRS),Metabolic Syndrome, or Metabolic Syndrome X. It is a disorder thatpresents risk factors for the development of Type II diabetes mellitusand cardiovascular disease including glucose intolerance,hyperinsulinemia and insulin resistance, dyslipidemia (eg, hightriglycerides and low HDL-cholesterol), hypertension and obesity.

[0005] Typical treatment of Type II diabetes mellitus and Syndrome Xfocuses on maintaining the blood glucose level as near to normal aspossible and includes diet and exercise, and when necessary, treatmentwith anti-diabetic agents, insulin or a combination thereof. TYPE IIdiabetes that cannot be controlled by dietary management is treated withoral antidiabetic agents including, but not limited to, sulfonylureas(e.g., not limited to first generation: chlorpropamide, tolazamide,tolbutamide; second generation: glyburide, glipizide; and thirdgeneration: glimepiride), biguanides (e.g., metformin),thiazolidinediones (e.g., rosiglitazone, pioglitazone, troglitazone),alpha-glucosidase inhibitors (e.g., acarbose, miglitol), meglitinides(e.g., repaglinide), other insulin-sensitizing compounds, and/or otheranti-obesity agents (e.g., orlistat or sibutramine). For Syndrome X, theanti-diabetic agents are additionally combined with pharmacologicalagents for the treatment of the concomitant co-morbidities (e.g.,antihypertensives for hypertension, hypolipidemic agents forhyperlipidemia).

[0006] First-line therapies typically include metformin andsulfonylureas as well as thiazolidinediones. Metformin monotherapy is afirst line choice, particularly for treating Type II diabetic patientswho are also obese and/or dyslipidemic. Lack of an appropriate responseto metformin is often followed by treatment with metformin incombination with sulfonylureas, thiazolidinediones, or insulin.Sulfonylurea monotherapy (including all generations of drugs) is also acommon first line option. Another first line therapy choice may bethiazolidinediones. Patients who do not respond appropriately to oralanti-diabetic monotherapy, are given combinations of these agents. Whenglycemic control cannot be maintained with oral antidiabetics alone,insulin therapy is used either as a monotherapy, or in combination withoral antidiabetic agents. These same strategies, optionally incombination with additional strategies (e.g., anti-hypertensive) can beused for the treatment of Syndrome X.

[0007] Anti-diabetic agents include, but are not limited to:

[0008] (a) Sulfonylureas, which increase insulin production bystimulating pancreatic beta cells, and therefore act as insulinsecretagogues. The primary mechanism of action of sulfonylureas is toclose ATP-sensitive potassium channels in the beta-cell plasma membrane,initiating a chain of events that result in insulin release. Suitableexamples of sulfonylureas include, but are not limited tochlorpropamide, tolazamide, tolbutamide, glyburide, glipizide,glimepiride, and like.

[0009] (b) Meglitinides, another class of insulin secretagogues, thathave a mechanism of action distinct from that of the sulfonylureas.Suitable examples of meglitinides include, but are not limited torepaglinide.

[0010] (c) Agents which modify insulin secretion such as Glucagon-likePeptide-1 (GLP-1) and it's mimetics, Glucose-insulinotropic peptide(GIP) and it's mimetics, Exendin and it's mimetics, and DipeptylProtease Inhibitors (DPPIV).

[0011] (d) Biguanides which decrease liver glucose production andincrease the uptake of glucose. Suitable examples include, but are notlimited to metformin.

[0012] (e) Thiazolidinediones, insulin sensitizing drugs which decreaseperipheral insulin resistance by enhancing the effects of insulin attarget organs and tissues. These drugs bind and activate the nuclearreceptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma)which increases transcription of specific insulin-responsive genes.Suitable examples of PPAR-gamma agonists are the thiazolidinedioneswhich include, but are not limited to rosiglitazone, pioglitazone,troglitazone, isaglitazone (known as MCC-555),2-[2-[(2R)-4-hexyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]ethoxy]-benzeneacetic acid, and the like. Additionally, the non-thiazolidinediones alsoact as insulin sensitizing drugs, and include, but are not limited toGW2570, and the like.

[0013] (f) Retinoid-X receptor (RXR) modulators, also insulinsensitizing drugs, which include, but are not limited to targretin,9-cis-retinoic acid, and the like.

[0014] (g) Other insulin sensitizing agents include, but are not limitedto INS-1, PTP-1B inhibitors, GSK3 inhibitors, glycogen phosphorylase ainhibitors, fructose-1,6-bisphosphatase inhibitors, and the like.

[0015] (h) Alpha-glucosidase inhibitors which act to inhibitalpha-glucosidase. Alpha-glucosidase converts fructose to glucose, thusthese inhibitors delay the digestion of carbohydrates. The undigestedcarbohydrates are subsequently broken down in the gut, thereby reducingthe post-prandial glucose peak. Suitable examples include, but are notlimited to, acarbose and miglitol.

[0016] (i) Insulins, including regular or short-acting,intermediate-acting, and long-acting insulins, inhaled insulin andinsulin analogues such as insulin molecules with minor differences inthe natural amino acid sequence. These modified insulins may have fasteronset of action and/or shorter duration of action.

[0017] (j) Small molecule mimics of insulin, including, but not limitedto L-783281, TE-17411, and the like.

[0018] (k) Na-glucose co-transporter inhibitors which inhibit the renalreabsorption of glucose such as T-1095, T-1095A, phlorizen, and thelike.

[0019] (l) Amylin agonists which include, but are not limited topramlintide, and the like.

[0020] (k) Glucagon antagonists such as AY-279955, and the like.

[0021] In addition to antidiabetic agents, therapies may include add-ontreatment with anti-obesity agents such as orlistat, a pancreatic lipaseinhibitor, which prevents the breakdown and absorption of fat; orsibutramine, an appetite suppressant and inhibitor of the reuptake ofserotonin, norepinephrine and dopamine in the brain. Other potentialadd-on anti-obesity agents include, but are not limited to,appetite-suppressants acting through adrenergic mechanisms such asbenzphetamine, phenmetrazine, phentermine, diethylpropion, mazindol,sibutramine, phenylpropanolamine or, ephedrine; appetite-suppressantagents acting through serotonergic mechanisms such as quipazine,fluoxetine, sertraline, fenfluramine, or dexfenfluramine;appetite-suppressant agents acting through dopamine mechanisms, eg,apomorphine; appetite-suppressant agents acting through histaminergicmechanisms (eg, histamine mimetics, H3 receptor modulators); enhancersof energy expenditure such as beta-3 adrenergic agonists and stimulatorsof uncoupling protein function; leptin and leptin mimetics; neuropeptideY antagonists; melanocortin-1, 3 and 4 receptor modulators;cholecystokinin agonists; glucagon-like peptide-1 (GLP-1) mimetics andanalogues (eg, Exendin); androgens (eg, dehydroepiandrosterone andderivatives such as etiocholandione), testosterone, anabolic steroids(eg, oxandrolone), and steroidal hormones; galanin receptor antagonists;cytokine agents such as ciliary neurotrophic factor; amylase inhibitors;enterostatin agonists/mimetics; orexin/hypocretin antagonists; urocortinantagonists; bombesin agonists; modulators of protein kinase A;corticotropin-releasing factor mimetics; cocaine- andamphetamine-regulated transcript mimetics; calcitonin-gene relatedpeptide mimetics; and fatty acid synthase inhibitors.

[0022] Add-on therapy using Compounds of Formula I:

[0023] has not, however, yet been contemplated in the art.

[0024] Such compounds are structurally novel antiepileptic compoundsthat are highly effective anticonvulsants in animal tests (MARYANOFF, B.E, NORTEY, S. O., GARDOCKI, J. F., SHANK, R. P. AND DODGSON, S. P. J.Med. Chem. 1987, 30, 880-887; MARYANOFF, B. E., COSTANZO, M. J., SHANK,R. P., SCHUPSKY, J. J., ORTEGON, M. E., AND VAUGHT J. L. Bioorg. Med.Chem. Lett. 1993, 3, 2653-2656; SHANK, R. P., GARDOCKI, J. F., VAUGHT,J. L., DAVIS, C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J.,NORTEY, S. O., MARYANOFF, B. E. Epilepsia 1994, 35, 450-460; MARYANOFF BE, COSTANZO M J, NORTEY S O, GRECO M N, SHANK R P, SCHUPSKY J J, ORTEGONM P, VAUGHT J L. J. Med. Chem. 1998, 41, 1315-1343). These compounds arecovered by three U.S. Pat. No. 4,513,006, No. 5,242,942, and No.5,384,327. One of these compounds2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate known astopiramate has been demonstrated in clinical trials of human epilepsy tobe effective as adjunctive therapy or as monotherapy in treating simpleand complex partial seizures and secondarily generalized seizures (E.FAUGHT, B. J. WILDER, R. E. RAMSEY, R. A. REIFE, L D. KRAMER, G. W.PLEDGER, R. M. KARIM et. al., Epilepsia 1995, 36 (S4), 33; S. K.SACHDEO, R. C. SACHDEO, R. A. REIFE, P. LIM and G. PLEDGER, Epilepsia1995, 36 (S4), 33; T. A. GLAUSER, Epilepsia 1999, 40 (S5), S71-80; R. C.SACHDEO, Clin. Pharmacokinet. 1998, 34, 335-346), and is currentlymarketed for the treatment of seizures in patients with simple andcomplex partial epilepsy and seizures in patients with primary orsecondary generalized seizures in the United States, Europe and mostother markets throughout the world. Despite the fact that topiramate,having the brand name Topomax® is widely marketed it has not been usedon an add-on therapy with anti-diabetic agents for treating Type IIDiabetes Mellitus or Syndrome X.

[0025] Compounds of Formula I were initially found to possessanticonvulsant activity in the traditional maximal electroshock seizure(MES) test in mice (SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS,C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., andMARYANOFF, B. E., Epilepsia 1994, 35, 450-460). Subsequent studiesrevealed that Compounds of Formula I were also highly effective in theMES test in rats. Topiramate was also found to effectively blockseizures in several rodent models of epilepsy (J. NAKAMURA, S. TAMURA,T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and. M. SASA,Eur. J. Pharmacol. 1994, 254, 83-89), and in an animal model of kindledepilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 1996, 24, 73-77).

[0026] More recently compounds of formula I have been found to beeffective for maintaining weight loss and in the treatment of obesity,as disclosed in U.S. Pat. No. 6,071,537 (WO 9800130). Thakur et al inWO9944581 disclose the use of topiramate for the treatment of diabetes.

DISCLOSURE OF THE INVENTION

[0027] It has now been found that compounds of the following formula(I):

[0028] wherein X is O or CH₂, and R¹, R², R³, R⁴ and R⁵ are as definedherein when administered in combination with one or more anti-diabeticagents, as defined herein, are useful in the treatment of Type IIDiabetes Mellitus and Syndrome X.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The sulfamates of the invention are of the following formula (I):

[0030] wherein

[0031] X is CH₂ or oxygen;

[0032] R¹ is hydrogen or alkyl; and

[0033] R², R³, R⁴ and R⁵ are independently hydrogen or lower alkyl and,when X is CH₂, R⁴ and R⁵ may be alkene groups joined to form a benzenering and, when X is oxygen, R² and R³ and/or R⁴ and R⁵ together may be amethylenedioxy group of the following formula (II):

[0034] wherein

[0035] R⁶ and R⁷ are the same or different and are hydrogen, lower alkylor are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.

[0036] R₁ in particular is hydrogen or alkyl of about 1 to 4 carbons,such as methyl, ethyl and iso-propyl. Alkyl throughout thisspecification includes straight and branched chain alkyl. Alkyl groupsfor R², R³, R⁴, R⁵, R⁶ and R⁷ are of about 1 to 3 carbons and includemethyl, ethyl, iso-propyl and n-propyl. When X is CH₂, R⁴ and R⁵ maycombine to form a benzene ring fused to the 6-membered X-containingring, i.e., R⁴ and R⁵ are defined by the alkatrienyl group ═C—CH═CH—CH═.

[0037] A particular group of compounds of formula (I) is that wherein Xis oxygen and both R² and R³ and R⁴ and R⁵ together are methylenedioxygroups of the formula (II), wherein R⁶ and R⁷ are both hydrogen bothalkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, inparticular where R⁶ and R⁷ are both alkyl such as methyl. A second groupof compounds is that wherein X is CH₂ and R⁴ and R⁵ are joined to form abenzene ring. A third group of compounds of formula (I) is that whereinboth R² and R³ are hydrogen.

[0038] The compounds of formula (I) may be synthesized by the followingmethods:

[0039] (a) Reaction of an alcohol of the formula RCH₂OH with achlorosulfamate of the formula ClSO₂NH₂ or ClSO₂NHR¹ in the presence ofa base such as potassium t-butoxide or sodium hydride at a temperatureof about −20° to 25° C. and in a solvent such as toluene, THF, ordimethylformamide wherein R is a moiety of the following formula (III):

[0040] (b) Reaction of an alcohol of the formula RCH₂OH withsulfurylchloride of the formula SO₂Cl₂ in the presence of a base such astriethylamine or pyridine at a temperature of about −40° to 25° C. in asolvent such as diethyl ether or methylene chloride to produce achlorosulfate of the formula RCH₂OSO₂Cl.

[0041] The chlorosulfate of the formula RCH₂OSO₂Cl may then be reactedwith an amine of the formula R¹NH² at a temperature of abut 40° to 25°C. in a solvent such as methylene chloride or acetonitrile to produce acompound of formula (I). The reaction conditions for (b) are alsodescribed by T. Tsuchiya et al. in Tetrahedron Lett., 1978, 3365.

[0042] (c) Reaction of the chlorosulfate RCH₂OSO₂Cl with a metal azidesuch as sodium azide in a solvent such as methylene chloride oracetonitrile yields an azidosulfate of the formula RCH₂OSO₂N₃ asdescribed by M. Hedayatullah in Tetrahedron Lett. 1975, 2455. Theazidosulfate is then reduced to a compound of formula (I) wherein R¹ ishydrogen by catalytic hydrogenation, e.g. with a noble metal and H₂ orby heating with copper metal in a solvent such as methanol.

[0043] The starting materials of the formula RCH₂OH may be obtainedcommercially or as known in the art. For example, starting materials ofthe formula RCH₂OH wherein both R² and R³ and R⁴ and R⁵ are identicaland are of the formula (II) may be obtained by the method of R. F. Bradyin Carbohydr. Res. 1970, 14, 35 or by reaction of the trimethylsilylenol ether of a R⁶COR⁷ ketone or aldehyde with fructose at a temperatureof about 25° C., in a solvent such a halocarbon, e.g. methylene chloridein the presence of a protic acid such as hydrochloric acid or a LewisAcid such as zinc chloride. The trimethylsilyl enol ether reaction isdescribed by G. L. Larson et al. in J. Org. Chem. 1973, 38, 3935.

[0044] Further, carboxylic acids and aldehydes of the formulae RCOOH andRCHO may be reduced to compounds of the formula RCH₂OH by standardreduction techniques, e.g. reaction with lithium aluminum hydride,sodium borohydride or borane-THF complex in an inert solvent such adiglyme, THF or toluene at a temperature of about 0° to 100° C., e.g. asdescribed by H. O. House in “Modern Synthetic Reactions”, 2nd Ed., pages45 to 144 (1972).

[0045] The compounds of formula I may also be made by the processdisclosed U.S. Pat. No. 4,513,006, No. 5,242,942, and No. 5,384,327,which are incorporated by reference herein.

[0046] The compounds of formula I include the various individual isomersas well as the racemates thereof, e.g., the various alpha and betaattachments, i.e., below and above the plane of the drawing, of R², R³,R⁴ and R⁵ on the 6-membered ring. Preferably, the oxygen of themethylenedioxy group (II) are attached on the same side of the6-membered ring.

[0047] Anti-diabetic agents useful for the treatment of Type II diabetesmellitus and Syndrome X include, but are not limited to, sulfonylureas,meglitinides, agents which modify insulin secretion, biguanides,thiazolidinediones, PPAR-gamma agonists, Retinoid-X receptor (RXR)modulators, insulin sensitizing agents, alpha-glucosidase inhibitors,insulins, small molecule mimics of insulin, Na-glucose co-transporterinhibitors, amylin agonists, glucagon antagonists, and the like.

[0048] Suitable examples of anti-diabetic agents include,chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide,glimepiride, repaglinide, metformin, rosiglitazone, pioglitazone,troglitazone, isaglitazone (known as MCC-555),2-[2-[(2R)-4-hexyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]ethoxy]-benzeneacetic acid, GW2570, targretin, 9-cis-retinoic acid, ascarbose,miglitol, L-783281, TE-17411, T-1095, BAY-279955, phlorizen,pramlintide, regular-acting insulin, short-acting insulin,intermediate-acting insulin, long-acting insulin, inhaled insulin,insulin analogues, acetohexamide, buformin, glibornuride, glyhexamide,glymidine, linogliride, palmoxirate, zopolrestat; etoformin,gilicalzide, glypinamide, and the like.

[0049] In addition to antidiabetic agents, add-on therapeutic agents mayinclude anti-obesity agents such as orlistat, sibutramine, mazindol,benzphetamine, phenmetrazine, phentermine, diethylpropion, mazindol,sibutramine, phenylpropanolamine, ephedrine, quipazine, fluoxetine,sertraline, fenfluramine, dexfenfluramine, apomorphine, Exendin,dehydroepiandrosterone, etiocholandione, testosterone, oxandrolone, andthe like. In addition, therapies may also include add-on treatment withanti-hypertensive agents and/or hypolipidemic agents.

[0050] As used herein, the terms “Syndrome X”, “Metabolic Syndrome” and“Metabolic Syndrome X” shall mean a disorder that presents risk factorsfor the development of Type II diabetes mellitus and cardiovasculardisease and is characterized by insulin resistance and hyperinsulinemiaand may be accompanied by one or more of the following: (a) glucoseintolerance, (b) Type II diabetes, (c) dyslipidemia, (d) hypertensionand (e) obesity.

[0051] The ability of the compounds of formula I administered incombination with an anti-diabetic agent to treat Type II diabetesmellitus and Syndrome X is based on the following case studies.

EXAMPLE 1 Case Study A (PT #2 ES)

[0052] The patient was a 59 year old female with a 6 year history ofType II diabetes. For the past four years the patient was being treatedwith insulin (70/30). At the start of treatment patient's weight was 236lbs, measured cholesterol was 316 mg/dl and measured glucose was 166mg/dl. The patient was started on Topiramate for treatment of seizuresand titrated to 75 mg a day. After 2 months of treatment, the patientindicated that her blood sugar had improved significantly to where shewas using the insulin less often. After 11 months, topira mate dosagewas increased to 200 mg b.i.d. After one year, the patient's weight was225 lbs and Hbg A1C was 6.94%. After 16 months, patient's fastingglucose was 89 mg/dl. After 18 months, patients indicated that homemeasured blood sugars were consistently less than 120 mg/dl, whereaspreviously blood sugars ranged between 150 and 160 mg/dl.

EXAMPLE 2 Case Study B (PT#3)

[0053] The patient was a 76 year old male with a 5 year history of TypeII diabetes. At the start of treatment, patient was taking 40 mg/dayGlucotrol (glipizide, a sulfonylurea) and weighed 293 lbs. The patientwas titrated on topiramate to 50 mg/day. After 1 month of treatment,patient reported that home measured blood sugars had dropped from abaseline of 300 mg/dl to measured blood sugars of 140 mg/dl. After 2months, the patient indicated average blood sugar levels of 80-140 mg/dland weight loss to 272 lbs.

EXAMPLE 3 Case Study C (PT #5 CL)

[0054] The patient was a 69 year old male with an 8 year history ofdiabetes. Prior to treatment, patient's weight was 201 lbs, Hgb A1C was9.3% and blood sugar was 309 mg/dl. Patient was taking Glucophage(metformin hydrochloride) at four 500 mg tablets/day (2 tablets in themorning, 1 tablet in the afternoon and 1 tablett at night, for a totalof 2000 mg/day), DiaBeta (glyburide) at at 10 mg twice a day (total of20 mg/day) and Rezulin (troglitazone) at 200 mg/day. Patient was startedon topiramate at 75 mg b.i.d (150 mg/day). Patient indicated that bloodsugars were “doing better”. Topiramate dosage was increased to 150 mgb.i.d (300 mg/day). at which time the patient was able to stopGlucophage due to improved sugar control. After 15 months patient'sweight was 190 lbs with blood sugars controlled on 100 mg topiramate inthe morning, 200 mg topiramate at night (Total of 300 mg/day), DiaBetaat 10 mg twice a day and Rezulin at 200 mg once a day.

EXAMPLE 4 Case Study D (PT #6 WD)

[0055] The patient was a 62 year old female, with a history of elevatedblood sugars and a weight of 188 lbs. At the time of initial treatment,patient's blood sugar was 426 mg/dl. Patient was started on topiramate,titrated to 100 mg once a day. The patient was also prescribed Amaryl(glimepiride). After 3 months, patient's blood sugar averaged in theupper 100s, lab sugars measured at 138 mg/dl, cholesterol at 278 mg/dl,triglycerides at 212 mg/dl and HgbA1C at 6.7%. After one year,topiramate dosage was increased to 200 mg/day with lab measured bloodsugars at 141 mg/dl, cholesterol at 200 mg/dl and triglycerides at 500mg/dl. Patient weighed 160 lbs. Patient was able to stop taking theAmaryl due to improved sugar control. Due to concerns about weight loss,topiramate was decreased to 100 mg/day. After 21 months, patient'sweight was 170 lbs, blood sugars were reported doing well. Lab measuredglucose was 115 mg/dl, cholesterol was measured at 236 mg/dl,triglycerides at 106 mg/dl and HgbA1C at 5.7%.

[0056] The above studies show that the oral administration of topiramatein combination with an anti-diabetic agent consistently improved thestatus of markers of diabetes mellitus, including blood glucose,glycosylated hemoglobin (Hgb Al C), and triglyceride levels.

[0057] Thus, for treating Type II diabetes mellitus or Syndrome X, acompound of formula I in combination with an anti-diabetic agent oragents may be employed comprising administering repeated oral doses ofthe compound of formula I in the range of about 25 to 300 mg once ortwice daily and repeated doses of the anti-diabetic agent or agents attherapeutically effective dosages. The therapeutically effective dosagefor anti-diabetic, anti-hypertensive and hypolipidemic agents disclosedherein may be readily determined by those skilled in the art based onstandard dosage guidelines.

[0058] As used herein, unless otherwise noted, the term “therapeuticallyeffective amount”, means that amount of active compounds orpharmaceutical agents that elicits the biological or medicinal responsein a tissue system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease or disorder beingtreated.

[0059] Wherein the present invention is directed to the administrationof a combination of one or more anticonvulsant derivatives and one ormore anti-diabetic or other pharmacological agents, “therapeuticallyeffective mount” shall mean that amount of the combination of agentstaken together so that the combined effect elicits the desiredbiological or medicinal response. For example, the therapeuticallyeffective amount of combination therapy comprising administration of acompound of formula (I) and an anti-diabetic agent would be the amountof the compound of formula (I) and the amount of the anti-diabetic agentthat when taken together or sequentially have a combined effect that istherapeutically effective. Further, it will be recognized by one skilledin the art that in the case of combination therapy with atherapeutically effective amount, as in the example above, the amount ofthe compound of formula (I) and/or the amount of the anti-diabetic agentindividually may or may not be therapeutically effective.

[0060] Wherein the present invention is directed to the administrationof a combination, the compounds may be co-administered by any suitablemeans, simultaneously, sequentially or in a single pharmaceuticalcomposition. Where the compounds are administered separately, the numberof dosages of each compound given per day, may not necessarily be thesame, e.g. where one compound may have a greater duration of activity,and will therefore, be administered less frequently.

[0061] The compound(s) of formula (I) and the anti-diabetic agent(s) maybe administered via the same or different routes of administration. Thecompound(s) of formula (I) and the anti-diabetic agent(s) may beadministered via the same or different routes of administration.Suitable examples of methods of administration are orally, intravenous(iv), intramuscular (im), and subcutaneous (sc). Compounds may also beadministrated directly to the nervous system including, but not limitedto the intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal and/or peri-spinal routes ofadministration by delivery via intracranial or intravertebral needlesand/or catheters with or without pump devices. The compound(s) offormula (I) and the anti-diabetic agent(s) may be administered accordingto simultaneous or alternating regimens, at the same or different timesduring the course of the therapy, concurrently in divided or singleforms.

[0062] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation andthe advancement of the disease condition. In addition, factorsassociated with the particular patient being treated, includingpatient's sex, age, weight, diet, time of administration and concomitantdiseases, will result in the need to adjust dosages.

[0063] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[0064] To prepare the pharmaceutical compositions of this invention, oneor more sulfamate compounds of formula (I) are intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,i.v. sterile injectable formulations will be prepared using appropriatesolubilizing agents. A unit dose would contain about 15 to 200 mg of theactive ingredient. Topiramate is currently available for oraladministration in round tablets containing 25 mg, 100 mg or 200 mg ofactive agent. The tablets contain some or all of the following inactiveingredients: lactose hydrous, pregelatinized starch, microcrystallinecellulose, sodium starch glycolate, magnesium stearate, purified water,carnauba wax, hydroxypropyl methylcellulose, titanium dioxide,polyethylene glycol, synthetic iron oxide, and polysorbate 80.

[0065] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

What is claimed is:
 1. A method for treating Type II diabetes mellitusin mammals afflicted with such condition comprising administering tosaid mammal a therapeutically effective amount of a compound of theformula I:

wherein X is CH₂ or oxygen; R¹ is hydrogen or alkyl; and R², R³, R⁴ andR⁵ are independently hydrogen or lower alkyl and, when X is CH₂, R⁴ andR⁵ may be alkene groups joined to form a benzene ring and, when X isoxygen, R² and R³ and/or R⁴ and R⁵ together may be a methylenedioxygroup of the following formula (II):

wherein R⁶ and R⁷ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring; in combination with a therapeutically effective amount of one ormore anti-diabetic agent.
 2. The method of claim 1 wherein the compoundof formula I is topiramate.
 3. The method of claim 1, wherein thetherapeutically effective amount of the compound of formula I is fromabout 32 to 512 mg.
 4. The method of claim 1, wherein thetherapeutically effective amount of the compound of formula I is of fromabout 16 to 256 mg once or twice daily.
 5. The method of claim 1 whereinthe anti-diabetic agent is selected from the group consisting of asulfonylurea, a meglitinide, an agents which modify insulin secretion, abiguanide, a thiazolidinedione, a peroxisome proliferator-activatedreceptor-gamma agonist (PPAR-gamma), a Retinoid-X receptor (RXR)modulator, an insulin sensitizing agent, an alpha-glucosidase inhibitor,an insulin, a small molecule mimics of insulin, Na a-glucoseco-transporter inhibitor, an amylin agonists and a glucagon antagonist.6. The method of claim 1 wherein the anti-diabetic agent is selectedfrom the group consisting of metformin, a sulfonylureas, athiazolidinediones and insulin.
 7. A method of treating Syndrome X(Insulin Resistance Syndrome, Metabolic Syndrome, or Metabolic SyndromeX) in mammals afflicted with such condition comprising administering tosaid mammal a therapeutically effective amount of a compound of theformula I:

wherein X is CH₂ or oxygen; R¹ is hydrogen or alkyl; and R², R³, R⁴ andR⁵ are independently hydrogen or lower alkyl and, when X is CH₂, R⁴ andR⁵ may be alkene groups joined to form a benzene ring and, when X isoxygen, R² and R³ and/or R⁴ and R⁵ together may be a methylenedioxygroup of the following formula (II):

wherein R⁶ and R⁷ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring; in combination with a therapeutically effective amount of one ormore anti-diabetic agent.
 8. The method of claim 8 wherein the compoundof formula I is topiramate.
 9. The method of claim 8, wherein thetherapeutically effective amount of the compound of formula I is fromabout 32 to 512 mg.
 10. The method of claim 8, wherein thetherapeutically effective amount of the compound of formula I is of fromabout 16 to 256 mg once or twice daily.
 11. The method of claim 8wherein the anti-diabetic agent is selected from the group consisting ofa sulfonylurea, a meglitinide, an agents which modify insulin secretion,a biguanide, a thiazolidinedione, a peroxisome proliferator-activatedreceptor-gamma agonist (PPAR-gamma), a Retinoid-X receptor (RXR)modulator, an insulin sensitizing agent, an alpha-glucosidase inhibitor,an insulin, a small molecule mimics of insulin, Na a-glucoseco-transporter inhibitor, an amylin agonists and a glucagon antagonist.12. The method of claim 1 wherein the anti-diabetic agent is selectedfrom the group consisting of metformin, a sulfonylureas, athiazolidinediones and insulin.